Thrombolysis and endovascular thrombectomy (ET), remain the only two FDA-approved ischemic stroke therapies. Despite the efficacy of ET, 50% of the patients remain disabled at 3 months. Adjunctive therapies to thrombolysis and ET are needed that provide ?bridging neuroprotection? and improve collateral blood flow. Since presence of collaterals is a major predictor of outcome with ET, a promising new therapeutic avenue is development of ?collateral therapeutics.? Remote ischemic conditioning (RIC), the simple and safe repetitive inflation-deflation of a blood pressure (BP) cuff on the limb, reduces infarct size, improves functional outcome, and improves cerebral and collateral blood flow in acute stroke. RIC can be administered in the ambulance, the helicopter, the Emergency Department, in the interventional suite, and in the hospital or rehabilitation facility and is therefore an ideal adjunctive treatment to ET. Our overall hypothesis is that RIC is an inexpensive, versatile, safe and effective therapy alone and in combination with tPA./ET in acute stroke. Our aims include: Aim 1: Working with the Coordinating Center and the Steering Committee, develop standard operation procedures, choice of stroke model, methods of randomization and blinding, sample size estimation and methods of data sharing Aim 2: Compare RIC and 5 other agents/interventions at optimal dosing regimens as adjunctive therapies to reperfusion in rodent acute stroke models in a pre-clinical multicenter randomized controlled trial (pRCT) design and advance the most effective intervention into phase II clinical trial.